Use of capecitabine after renal allograft transplantation in dog erythrocyte antigen-matched dogs

OBJECTIVES: To investigate the use of a capecitabine (CAP)-based regimen after renal transplantation in dogs. STUDY DESIGN: Prospective, pilot study. ANIMALS: Healthy, unrelated, dog erythrocyte antigen (DEA)-matched, adult beagles. METHOD: Standard heterotopic renal transplantation with native nephrectomy was performed in 7 dogs. Dogs received oral, twice daily, CAP (250 mg/m2), cyclosporine-A (CsA) (4 mg/kg), ketoconazole (5 mg/kg), and prednisolone (0.25 mg/kg). After 90 days the surviving dogs were euthanatized and complete necropsy was performed. RESULTS: Seven transplants were performed. All dogs survived surgery. Six dogs had acute neurotoxicity, which resulted in death or euthanasia of 2 dogs within 2 days of surgery. In the remaining dogs, toxicity resolved rapidly with cessation of drug administration. Thereafter, modification of the regimen minimized toxicity. The 5 remaining dogs survived to study end; 4 dogs had no evidence of graft rejection. Necropsy examination was mostly unremarkable in all dogs. There were no major changes in CBC or biochemical values, except for a significant increase in serum calcium. CONCLUSIONS: CAP appeared well tolerated in most dogs. Toxicity occurred but abated with modification of the drug regimen. Efficacy for postoperative immunosuppression cannot be determined by this study, although results are promising. CLINICAL RELEVANCE: CAP-CsA-prednisolone is an effective, oral immunosuppressive regimen for prevention of acute allograft rejection in DEA-matched beagles. Further studies on dose, toxicity, and efficacy compared with current immunosuppressive regimens are needed before use in clinical practice.     

An evaluation of combined immunosuppression with MNA 715 and microemulsified cyclosporine on renal allograft rejection in mismatched mongrel dogs

OBJECTIVE: To evaluate a combination of MNA 715 and microemulsifed cyclosporine for the prevention of renal allograft rejection in mismatched mongrel dogs. STUDY DESIGN: Randomized, experimental study. ANIMALS: Fourteen female mismatched mongrel dogs. METHODS: Heterotopic renal transplantation and bilateral nephrectomy were performed in each dog. Dogs were randomly assigned to receive either MNA 715 and cyclosporine (n = 8) or cyclosporine alone (n = 6). Dogs were killed at 100 days after transplantation or when plasma creatinine exceeded 7 mg/dL. RESULTS: In the cyclosporine and MNA 715 group: 4 dogs survived to 100 days with normal plasma creatinine concentrations; 2 dogs with intestinal intussusceptions were killed at 5 and 8 days, 1 dog with a wound infection and sepsis was killed at 14 days, and 1 dog with a serum creatinine concentration >7 mg/dL was killed at 51 days postoperatively. In the cyclosporine-alone group: 3 dogs with acute rejection were killed at 6 to 9 days and 3 dogs survived to 100 days. In dogs treated with cyclosporine and MNA 715, survival to histologically confirmed acute rejection was significantly longer (P =.044) and the degree of mononuclear cell infiltration was significantly reduced (P =.040), compared with dogs treated with cyclosporine alone. CONCLUSIONS: MNA 715 combined with cyclosporine prolonged allograft survival and reduced the severity of histologic rejection in a clinically relevant renal transplant model. CLINICAL RELEVANCE: An immunosuppressive regimen consisting of MNA715 and microemulsified cyclosporine may be effective in preventing allograft rejection in canine renal transplant patients.     

Acute vascular and interstitial rejection following renal allograft transplantation in dogs

Renal allograft transplantation was performed in four beagles. Immunosuppressive treatment using cyclosporine, mizoribin and prednisolone was continued from Day 5 pre- until Day 20 post-transplantation. Between Days 28 and 32 post-transplantation, an abrupt elevation of the serum creatinine values followed by the development of uremia was seen in all recipients. Histopathology of the allografts examined between Days 28 and 37 revealed edema, necrosis, hemorrhage and severe diffuse interstitial cellular infiltration as well as tubulitis. Glomerular changes notably included swelling of the tufts due to hypercellularity, which was consistent with transplant glomerulitis. The intrarenal arteries exhibited fibrinoid necrosis of the walls and intimal or transmural cellular infiltration. These renal lesions were consistent with those of acute vascular and interstitial rejection in humans.     

Microemulsified cyclosporine-based immunosuppression for the prevention of acute renal allograft rejection in unrelated dogs: preliminary experimental study

OBJECTIVES: To determine whether the microemulsified formulation of cyclosporine (MCsA; Neoral; Novartis A.G.), combined with azathioprine (Imuran; Glaxo Wellcome), and prednisolone (Delta-Cortef; Upjohn), would be effective in preventing acute renal allograft rejection in unrelated mongrel dogs. To document any toxic effects associated with this drug combination. STUDY DESIGN: rospective, pilot study. ANIMALS: Four healthy, adult, mongrel, canine renal allograft recipients. METHODS: Heterotopic renal transplantation, with bilateral nephrectomy, was performed in 4 dogs. Allografts were harvested from 2 unrelated dogs that were to be euthanatized for reasons unrelated to this study. The dogs were treated for 100 days or until signs of illness or allograft rejection required euthanasia. Microemulsified cyclosporine (20 mg/kg/day), azathioprine (5 mg/kg every other day), and prednisolone (1 mg/kg/day) were administered for the prevention of acute rejection. Body weight, serum biochemistry profiles, complete blood counts, and trough whole-blood cyclosporine concentrations were measured throughout the study. Cyclosporine dose was adjusted to maintain a trough concentration of 400-500 ng/mL. Azathioprine dose was decreased if evidence of hepatotoxicity developed or if the total blood white cell count was <4,000 cells/micro L. The prednisolone was tapered by 0.25 mg/kg increments every 3 weeks and discontinued 14 days before the end of the study in the surviving dogs. Complications were recorded. A complete necropsy and histopathologic examination were performed in each recipient. RESULTS: Two of the 4 dogs survived the 100-day period. One dog was euthanatized at 8 days because of an intestinal intussusception. One dog was euthanatized at 64 days because of a severe upper respiratory infection. At the time of death, these 2 dogs had plasma creatinine concentrations of 1.5 and 2.6 mg/dL, respectively, with no histopathologic evidence of allograft rejection. All dogs had transient weight loss (range, 4.6%-17.7% of preoperative body weight) between days 7 and 14. Two dogs had evidence of hepatotoxicity. The 2 dogs surviving to 100 days had normal serum creatinine concentrations and no clinical signs of rejection. One of these dogs had evidence of a grade IIa acute/active rejection based on the modified BANFF 97 histopathologic classification. The second dog had no evidence of rejection or inflammation within the allograft. CONCLUSIONS: This preliminary experimental study shows that immunosuppression using MCsA, combined with azathioprine and prednisolone, may be effective in preventing acute renal allograft rejection in unrelated mongrel dogs for 100 days. Complications included ileocolic intussusception, upper respiratory infection, weight loss, and transient hepatotoxicity. CLINICAL RELEVANCE: Immunosuppression using MCsA, azathioprine, and prednisolone may be effective in preventing acute renal allograft rejection in unrelated, mongrel dogs. This triple drug protocol is cost-effective and was easy to administer. Further investigation is warranted to minimize toxic effects and to determine the efficacy of prophylactic renal biopsies to detect and treat subclinical acute/active rejection.     

Renal allograft histopathology in dog leukocyte antigen mismatched dogs after renal transplantation

OBJECTIVE: To evaluate allograft histopathology in dog leukocyte antigen (DLA)-mismatched dogs undergoing renal transplantation, with transient immunosuppression. STUDY DESIGN: Prospective study. ANIMALS: Ten healthy adult mongrel dogs. METHODS: Reciprocal renal transplantation and bilateral nephrectomy were performed. Immune conditioning consisted of nonmyeloablative (200 cGy), total body irradiation (TBI), bone marrow transplantation (BMT; 7 dogs), cyclosporine (CSA; 15 mg/kg every 12 hours), mycophenolate mofetil (MMF; 10 mg/kg every 12 hours) and intermittent prednisone (1 mg/kg every 12-24 hours). Biopsies were collected at transplantation, during full immunosuppression (44-90 days), and once medications were reduced or discontinued (228-580 days). Biopsies were evaluated for interstitial, tubular, vascular, and glomerular lesions. Blood urea nitrogen, creatinine, serum CSA concentrations, and clinical score were determined at each biopsy. RESULTS: Seven dogs survived >200 days (mean, 380 days). Transient CSA toxicity was suspected in 6 dogs. Lymphocytic, plasmacytic interstitial inflammation, and tubulitis progressed when immunosuppressive medications were decreased. All 7 dogs had histologic lesions consistent with some degree of allograft rejection at study end. CONCLUSION: Nonmyeloablative TBI, BMT, and short-term immunosuppression with CSA, MMF, and prednisone allowed renal allograft function and dog survival for >200 days. It appears unlikely that total drug withdrawal will be possible in unrelated DLA-mismatched dogs using this protocol. CLINICAL RELEVANCE: Transient immunosuppression with MMF, CSA, and prednisone along with BMT and nonmyeloablative TBI may make kidney transplantation a clinical reality for treatment of kidney failure in dogs. Initiating both MMF and CSA at lower dosages may potentially eliminate early renal allograft injury.     

Pharmacokinetics of disodium-fosfomycin in mongrel dogs

Pharmacokinetic variables of fosfomycin were determined after administration of buffered disodium-fosfomycin intravenously (IV), intramuscularly (IM), subcutaneously (SC) and orally (PO), in mongrel dogs, at 40 and 80 mg/kgday for three days. Renal integrity was also assessed by measuring key serum variables. Day 1, day 2 and day 3 plasma concentration vs. time profiles were undistinguishable, but there appears to be a lineal increase in serum concentrations vs. time with the dose. A non-accumulative kinetic behavior was observed after three days with both doses and most pharmacokinetic variables remain unaltered. Considering a MIC range from 1 mirog/mL to 16 microg/mL of fosfomycin in serum for sensitive bacteria, and a negligible plasma protein binding of fosfomycin (<0.5%), useful plasma concentrations can only be achieved after the SC injection of 80 mg/kg every 12h, having a C(max)=18.96+/-0.3 microg/mL; a T(1/2beta)=2.09+/-0.06 microg/mL and a bioavailability of 84-85%. No alterations were observed in serum variables of kidney-related biochemical values.     

Use of taste repellants and emetics to prevent accidental poisoning of dogs

Twelve taste repellents and 3 oral emetics were tested. The taste repellents were capsaicin, capsicum, oleoresin, sucrose octaacetate, quinine tonic, quassia wood extract, vanillamide, horseradish extract, caffeine, pepperoni enhancer, acorn extract, and commercially available bitter and hot flavors. The emetics tested were: antimony potassium tartrate, apomorphine, and copper sulfate. Intake of a 20% sucrose solution by Beagles was significantly depressed by addition of vanillamide at concentrations greater than 0.001%, by capsicum and capsaicin at concentrations greater than 0.01%, and by horseradish extract, pepperoni enhancer, and a commercially available hot flavor at concentrations greater than 0.1%. Antimony potassium tartrate, when added to the 20% sucrose solution at a concentration of 0.1%, produced emesis as did apomorphine at a concentration of 0.005% and copper sulfate at 1%. When the emetic antimony potassium tartrate was combined with vanillamide in a 20% sucrose solution, intake was reduced to less than 20 ml, and vomiting occurred within 15 minutes. Capsaicin (0.02%) inhibited intake of ethylene glycol to less than the lethal dose in 5 dogs tested. Incorporation of such taste repellents and/or emetics into potentially poisonous substances would reduce accidental poisoning of animals and children.     

Gentamicin-associated acute renal failure in the dog

Gentamicin-associated acute renal failure was diagnosed in 10 dogs. The disease was characterized by a poor prognosis and lengthy hospitalization. Hypoalbuminemia, disorders of potassium homeostasis, proteinuria, hematuria, and cylindruria were common during therapy for renal failure. Fever and dehydration were the most commonly identified potential predisposing factors.     

Cardiovascular effects of pancuronium bromide in mongrel dogs.

The cardiovascular effects of a new nondepolarizing muscle relaxant, pancuronium bromide, were studied in mongrel dogs. Small, but significant, increases in mean arterial blood pressure were observed after each of 2 intravenous doses (0.01 mg/kg and 0.1 mg/kg) were given. Heart rate increased significantly in dogs administered the larger dosage, and indexes of ventricular functions demonstrated a trend toward positive cardiac inotrophy after either the large or the small dose.     

Use of dopamine in acute renal failure

Objective: To review the current understanding of dopamine and its use in the prevention and treatment of acute renal failure (ARF). Data sources: Original research articles and scientific reviews. Human data synthesis: Low‐dose dopamine administration has been shown to increase natriuresis and urinary output in both healthy individuals and in a few small studies in human patients with renal insufficiency. However, in several large meta‐analyses, dopamine treatment did not change mortality or the need for dialysis. Due to the potential side effects, the use of dopamine for prevention and treatment of ARF is no longer recommended in human medicine. Veterinary data synthesis: Low‐dose dopamine increases urinary output in healthy animals and animal models of ARF if given before the insult. There are no available studies looking at the effect of low‐dose dopamine therapy in naturally occurring ARF in dogs or cats. Conclusion: Due to the potential side effects of low‐dose dopamine therapy, the results from large human trials, and the lack of information in veterinary medicine, the use of dopamine for treatment of ARF in veterinary patients should be further evaluated.     

Hemodialysis of a dog with acute renal failure

A dog with oliguric acute renal failure presumed to have been caused by ethylene glycol ingestion was treated by hemodialysis for 1 month. Hemodialysis was effective in controlling azotemia, hyperphosphatemia, and hyperkalemia when performed on a daily or alternate-day basis. The major complications during treatment were infection and severe weight loss. Serial renal biopsies disclosed a progression from initial acute tubular necrosis to severe diffuse interstitial fibrosis and mononuclear cell inflammation. Infection, cachexia, development of end-stage renal lesions, and terminal hyperkalemia contributed to the eventual death of the dog.     

Prevalence of dog erythrocyte antigen 1.1 in dogs in Switzerland evaluated with the gel column technique

Canine blood typing has become an established and essential laboratory test due to the rising demand for safe and efficient blood transfusions. The most immunogenic and clinically important blood type is DEA 1.1. Little is known about DEA 1.1 frequencies or special characteristics among different canine breeds. 304 dogs were tested for DEA 1.1. DEA 1.1-typing was performed using a commercial gel column technique (ID-Gel Test Canine DEA 1.1, DiaMed, Cressier, Switzerland). Fifty-three percent of all tested dogs reacted positive for DEA 1.1, whereas 49 % of the mixed breeds tested DEA 1.1-positive. All Bernese mountain dogs (n = 22) and Rottweilers (n = 9) tested positive for DEA 1.1, while all Boxers (n = 8), Flat-Coated Retrievers (n = 9), and Border Collies (6) tested negative for DEA 1.1. The prevalence of DEA 1.1 in dogs in Switzerland was found to be comparable to that reported from other countries. The tested breeds were found to differ considerably in the frequency of DEA 1.1. This knowledge is useful for selection of blood donors. However, DEA 1.1 blood typing of donor and recipient prior to transfusion and cross matching in sensitized dogs is unavoidable.